CN117618573B - ERR-gamma modulators and their use in the treatment of diabetes - Google Patents
ERR-gamma modulators and their use in the treatment of diabetes Download PDFInfo
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Abstract
The invention relates to the technical field of biological medicines, and provides an ERR-gamma regulator and application thereof in treatment of diabetes. The invention discovers that ERR-gamma gene expression is related to diabetes for the first time, and can be used for treating the diabetes by regulating ERR-gamma expression in patients. The specific ERR-gamma regulator is provided, so that ERR-gamma can be efficiently regulated down, the blood sugar content of diabetics is reduced, the insulin content of the diabetics is improved, the blood sugar storage and conversion functions of the diabetics are recovered, and reference significance is provided for the treatment of diabetes.
Description
Technical Field
The invention relates to the technical field of biological medicines, in particular to an ERR-gamma regulator and application thereof in diabetes treatment.
Background
Diabetes is a metabolic disease characterized by hyperglycemia. Hyperglycemia is caused by defective insulin secretion or impaired biological action, or both. Long-standing hyperglycemia leads to chronic damage, dysfunction, of various tissues, especially the eyes, kidneys, heart, blood vessels, nerves.
Currently, diabetes is one of four major non-infectious diseases in the world, and conventional drug therapy often results in enormous medical costs, psychological distress, and physical affliction. Great efforts are made to find new therapeutic targets and to develop new drugs for the treatment of diabetes, but new findings and treatments are still needed.
One of the candidate classes of new drugs is small interfering RNAs, which have been investigated as novel therapeutic agents for the treatment of various disorders. Methods of small interfering RNA-based therapies include introducing synthetic small interfering RNAs into a subject to trigger RNA interference, thereby inhibiting mRNA expression of a particular gene to produce gene silencing or inhibition. Thus, it is desirable to provide new therapies for diabetes that are economical, persistent or less physically damaging.
Disclosure of Invention
Aiming at the technical problems existing in the prior art, the invention provides an ERR-gamma regulator and application thereof in diabetes treatment. The invention designs a regulator for targeting down regulation aiming at ERR-gamma gene for the first time, and achieves the aim of treating diabetes by silencing ERR-gamma.
Further, the ERR-gamma modulator is used for realizing the down regulation of ERR-gamma genes or proteins thereof through an RNA interference mode. The ERR-gamma regulator is selected from any one of the following:
1) Downregulating ERR-gamma gene or protein thereof by RNA interference;
2) Down-regulation of the ERR-gamma gene or protein thereof is achieved by neutralizing antibodies.
Still further, the RNA interference mode comprises siRNA and shRNA.
Still further, the RNA interference mode is siRNA.
Further, the siRNA is one or more selected from siRNA1-3, and the corresponding sequences are shown in SEQ ID NO. 5-10.
It is another object of the present invention to provide the use of ERR-gamma modulators for the preparation of a medicament for the treatment of diabetes.
Further, the ERR-gamma modulator achieves the aim of treating diabetes by targeting down-regulating ERR-gamma.
Further, the heavy chain variable region sequence of the neutralizing antibody is shown as SEQ ID NO.8, and the light chain variable region sequence is shown as SEQ ID NO. 9.
Further, the neutralizing antibody heavy chain variable region comprises CDR1, CDR2 and CDR3, the sequences of which correspond to those shown in SEQ ID NOS.10-12, respectively.
Further, the light chain variable region includes CDR4, CDR5 and CDR6, which sequences correspond to SEQ ID NO.13-15, respectively.
Further, the diabetes is not limited to type 1 diabetes and type 2 diabetes.
It is another object of the present invention to provide a pharmaceutical composition for treating diabetes, characterized in that the pharmaceutical composition comprises an inhibitor of ERR-gamma gene and/or its expression product.
Further, the inhibitor is an siRNA directed against ERR- γ.
The invention has the following advantages: the invention discovers that ERR-gamma gene expression is related to diabetes for the first time, and can be used for treating diabetes by regulating ERR-gamma expression in patients; the specific ERR-gamma regulator is provided, so that ERR-gamma can be efficiently regulated down, the blood sugar content of diabetics is reduced, the insulin content of the diabetics is improved, the blood sugar storage and conversion functions of the diabetics are recovered, and reference significance is provided for the treatment of diabetes.
Drawings
FIG. 1. Analysis of ERR-gamma gene differential expression in diabetic patients;
FIG. 2. ERR-gamma protein differential expression analysis in diabetic patients;
FIG. 3 analysis of silencing efficacy of different siRNAs on ERR-gamma gene.
Detailed Description
The present invention will be described in further detail with reference to specific examples so as to more clearly understand the present invention by those skilled in the art.
Example 1
Differential analysis of ERR-gamma gene expression in diabetic and normal populations: serum of 100 diabetics and 100 normal people is collected, total RNA of the diabetics and normal people is extracted by using Qiagen trace sample total RNA extraction kit 74004, reverse transcription of RNA is performed by using a reverse transcription kit of TAKARA company, and the expression condition of ERR-gamma genes is analyzed by qPCR.
Wherein, QPCR amplification primers are designed according to the coding sequences of ERR-gamma gene (NM_ 001243519.2) and GAPDH gene in Genbank, and are synthesized by Shanghai Bioengineering technical service Co. The specific primer sequences are as follows:
ERR-gamma gene:
the forward primer is 5'-ATGGATTCGGTAGAACTTTG-3' (SEQ ID NO. 1);
the reverse primer is 5'-CAGCTATAGACATGGTTTTA-3' (SEQ ID NO. 2),
GAPDH gene:
the forward primer is 5'-TAACTCTGGTAAAGTGGAT-3' (SEQ ID NO. 3);
The reverse primer is 5'-GGAATCATATTGGAAC-3' (SEQ ID NO. 4).
QPCR reaction system: the forward and reverse primers (10. Mu. Mol/L) were 1. Mu.l each, 12.5. Mu.l of SYBR Green polymerase chain reaction system, 2. Mu.l of cDNA template, and the remainder were made up to 20. Mu.l with ddH 2O.
QPCR reaction conditions: 95 ℃ for 10min, (95 ℃ for 30s,60 ℃ for 50s,72 ℃ for 40 s) 45 cycles, 72 ℃ for 10min.
And the relative quantification is carried out by adopting a 2delta delta CT method, each group of experiments are repeated for 3 times, the result data are expressed in the mode of mean value plus or minus standard deviation, SPSS13.0 statistical software is adopted for statistical analysis, and the difference between the two is adopted for t-test, so that the statistical significance is realized when P is less than 0.05.
As a result, as shown in FIG. 1, the ERR-gamma gene expression level in the serum of diabetic patients was significantly increased compared with that of normal persons, and the difference was statistically significant (P < 0.05).
Example 2
ERR-gamma protein differential analysis in diabetic and normal populations: and detecting ERR-gamma protein difference conditions of diabetics and normal people by using a western blot method. And analyzing the gray value of the protein band by using imageJ software, and normalizing the gray value of the ERR-gamma protein band by taking beta-actin as an internal reference. Each set of experiments was repeated 3 times and the data of the results were expressed as mean ± standard deviation, statistically analyzed using SPSS13.0 statistical software, and the differences between the two were determined by t-test, which was considered statistically significant when P < 0.05.
The results are shown in FIG. 2, where ERR-gamma protein content in serum of diabetics is significantly increased compared to normal persons, and the difference is statistically significant (P < 0.05).
Example 3
Analysis of the influence of ERR-gamma protein on fasting blood glucose and insulin content of mice: SPF-grade healthy male ICR mice were selected 40 and divided into an experimental group and a control group, wherein the mice in the experimental group were fed with basal feed +10mg/kg ERR-gamma protein, and the mice in the control group were fed with basal feed only. After feeding for one week, each group of mice is fasted without water control for 5h treatment, and the fasting blood glucose level is detected by tail breaking and blood taking; then, the eyeballs are picked up for blood collection, and the fasting serum insulin level is detected by adopting a radioimmunoassay.
The statistical results are shown in the following table: compared with the control group, the ERR-gamma protein added into the basic feed can cause the blood sugar content of mice to be increased sharply, and the insulin content is also increased. Furthermore, ERR-gamma protein is proved to be involved in the generation and metabolism of blood sugar.
TABLE 1 analysis of the influence of ERR-gamma protein on fasting blood glucose and insulin content in mice
Example 4
To further understand the effect of ERR-gamma on diabetes, the inventors continued to design three sirnas for ERR-gamma. And constructing db/db diabetic mouse model, and dividing it into four groups uniformly. Wherein the first group is a control group to which only physiological saline is administered during the whole process; the second group was administered siRNA-1, the third group was administered siRNA-2, the fourth group was administered siRNA-3, and the three groups were delivered by intravenous injection using lipid carrier LP 171. The administration was performed at two days intervals, each dose being 1 mg/kg/dose, for 3 weeks. After the end of the administration, the blood glucose content and the insulin content in the mice models of the experimental group and the control group were detected, and the silencing efficiency of the three siRNAs on ERR-gamma was analyzed.
Wherein, siRNA-1:5'-GGUAGAGGUCUGCCUCAGGA-3' (SEQ ID NO. 5);
siRNA2：5’-UGCUGGAGCACACAGUAUGG-3’(SEQ ID NO.6)，
siRNA3：5’-GCUUGUACUUCUGCCGACCU-3’(SEQ ID NO.7)
As shown in FIG. 3, the siRNA1-3 of the present invention can achieve the purpose of silencing ERR-gamma with high efficiency, and compared with the control group, after intravenous injection of siRNA1-3, the blood sugar content in the mouse model is obviously reduced, and the insulin content shows an ascending trend compared with the control group (Table 2), further confirming that the treatment of diabetes can be achieved by targeted inhibition of the expression level of ERR-gamma gene.
TABLE 2 silencing the effect of ERR-gamma on blood glucose and insulin in mice
Example 5
Based on example 4, the inventors continued to prepare neutralizing antibodies against ERR-gamma protein as immunogen via hybridoma cell technology. The heavy chain variable region sequence of the neutralizing antibody is shown as SEQ ID NO.8, and the light chain variable region sequence is shown as SEQ ID NO. 9.
Further, the heavy chain variable region of the neutralizing antibody comprises CDR1, CDR2 and CDR3, the sequences of which correspond to those shown in SEQ ID NO.10-12, respectively. The light chain variable region comprises CDR4, CDR5 and CDR6, the sequences of which correspond to SEQ ID NO.13-15, respectively.
Further knowing the effect of ERR-gamma on diabetes, the inventors continued to construct a db/db diabetic mouse model, which was evenly divided into two groups. Wherein the first group is a control group to which only physiological saline is administered during the whole process; the second group was given by intravenous injection of neutralizing antibodies at a dose of 5mg/kg at 1 week intervals, each dose being 1 mg/kg/dose for 3 weeks. After the end of the administration, ERR-gamma protein content in the mice models of the experimental group and the control group was detected and analyzed
Blood glucose content and insulin content.
TABLE 3 silencing ERR-gamma effects on blood glucose and insulin in mice
As shown in Table 3, the neutralizing antibody of the present invention can effectively reduce the ERR-gamma protein content in db/db diabetic mouse model, so that it can recover the ERR-gamma protein content at the same level as that of healthy mice. And compared with the control group, after intravenous injection of the neutralizing antibody, the blood sugar content in the mouse model is obviously reduced, and the insulin content is obviously increased compared with the control group, so that the treatment of diabetes can be further proved to be realized by targeted inhibition of ERR-gamma protein.
The above-described embodiments are provided to illustrate the gist of the present invention, but are not intended to limit the scope of the present invention. It will be understood by those skilled in the art that various modifications and equivalent substitutions may be made to the technical solution of the present invention without departing from the spirit and scope of the technical solution of the present invention.
Claims (5)
1. An ERR-gamma modulator, wherein the ERR-gamma modulator is used to down-regulate the expression level of an ERR-gamma gene or protein thereof;
the ERR-gamma regulator is used for realizing downregulation of ERR-gamma genes or proteins thereof in an RNA interference mode;
The RNA interference mode is siRNA;
The siRNA is one or more selected from siRNA1-3, and the corresponding sequence is shown in SEQ ID NO. 5-7.
2. Use of an ERR-gamma modulator of claim 1 in the manufacture of a medicament for the treatment of diabetes.
3. The use of claim 2, wherein the ERR- γ modulator is for the purpose of treating diabetes by targeted down-regulation of ERR- γ.
4. The use according to claim 3, wherein the diabetes is not limited to type 1 diabetes and type 2 diabetes.
5. A pharmaceutical composition for the treatment of diabetes, characterized in that it comprises an inhibitor of the ERR-gamma gene and/or its expression product;
The inhibitor is an siRNA against ERR- γ;
The siRNA is one or more selected from siRNA1-3, and the corresponding sequence is shown in SEQ ID NO. 5-7.
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| KR101311534B1 (en) * | 2010-12-27 | 2013-09-25 | 전남대학교산학협력단 | A composition for treating or preventing diabetes comprising 4-hydroxy tamoxifen analog or pharmaceutically acceptable salts thereof as an effective ingredient |
| AU2015235922B2 (en) * | 2014-03-27 | 2021-07-01 | Salk Institute For Biological Studies | Compositions and methods for treating type 1 and type 2 diabetes and related disorders |
| CN105753753A (en) * | 2016-04-12 | 2016-07-13 | 复旦大学附属华山医院 | Compound for adjusting activity of estrogen-related receptor and medical application of compound |
| KR101902512B1 (en) * | 2017-04-24 | 2018-10-01 | 연세대학교 산학협력단 | Method and kit for assessing risk of diabetes using esrrg genetic polymorphism |
| EP3863659A4 (en) * | 2018-10-12 | 2022-07-13 | Salk Institute for Biological Studies | Cells, islets, and organoids that evade immune detection and autoimmunity, methods of production and use thereof |
| US20230017330A1 (en) * | 2019-11-26 | 2023-01-19 | Novmetapharma Co., Ltd. | USE OF COMPOSITION FOR ENHANCING ANTICANCER EFFECT, COMPRISING ERRy INHIBITOR AS ACTIVE INGREDIENT |
| CN112481216A (en) * | 2020-11-09 | 2021-03-12 | 山东新医学中西医结合医学研究院有限公司 | Human induced pluripotent stem cell and culture method and application thereof |
| KR102412352B1 (en) * | 2020-11-17 | 2022-06-23 | 충남대학교산학협력단 | Pharmaceutical Composition for Treatment of Leukemia Comprising ERR-α Antagonist |
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| Orphan Nuclear Receptor Estrogen-Related Receptor γ (ERRγ) Is Key Regulator of Hepatic Gluconeogenesis;Kim, DK等;JOURNAL OF BIOLOGICAL CHEMISTRY;20120622;第287卷(第26期);第21628-21639页 * |
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